Influenza A viruses (IAV) are significant human pathogens causing yearly epidemics and occasional pandemics. Past pandemics have resulted in significant morbidity and mortality. The 1918 influenza pandemic was thought to have resulted in the death of at least 675,000 people in the U.S., and 40 million people worldwide. Pandemics in 1957 and 1968, while less severe, were also of major public health importance. A novel influenza A virus of swine origin became pandemic in 2009, causing the first pandemic in 41 years. In addition, annual epidemic influenza causes are also very significant resulting in up to 80,000 deaths in the US annually. Highly pathogenic avian H5N1 viruses continue to circulate enzootically in poultry in many countries and continue to cause human infections. Recently a novel avian H7N9 strain emerged in China also causing human infections and fatalities. A variety of experimental pathogenesis studies to model host adaptation, map viral virulence factors and host factors in disease progression, evaluate novel therapeutics and vaccines were performed. Influenza virus infections are a global public health problem, with a significant impact of morbidity and mortality from both annual epidemics and pandemics. The current strategy for preventing annual influenza is to develop a new vaccine each year against specific circulating virus strains. Because these vaccines are unlikely to protect against an antigenically divergent strain or a new pandemic virus with a novel hemagglutinin (HA) subtype, there is a critical need for vaccines that protect against all influenza A viruses, a so-called universal vaccine. Recent work has suggested that such broadly protective, or universal, influenza virus vaccines might be achievable using vaccine strategies that target conserved B- and T-cell epitopes. Efforts to develop broadly protective influenza virus vaccines were emphasized during the reporting period. A vaccine cocktail expressing four low pathogenicity avian influenza virus hemagglutinin (HA) subtypes (H1, H3, H5, and H7) has proven very efficacious in mouse and ferret studies. Initial studies using HA-expressing VLPs produced in bacculovirus have been promising. More recently, vaccines consisting of mixtures of inactivated low pathogenicity avian influenza viruses expressing different HA subtypes have also been shown to be very promising as broadly protective vaccines when delivered either intramuscularly or intransally. These vaccine cocktails provide 100% protection against lethal challenge with heterosubtypic influenza A viruses in mice and significant protection in ferret studies, and result in the development of antibodies against the hemagglutinin head and stalk, antibodies to neuraminidases, along with an increase in CD8+ influenza-specific T cells.